HYPERHOMOCYSTEINEMIA AND ITS IMPLICATIONS IN

ATHEROSCLEROSIS – THE INDIAN SCENARIO

Moderator – Dr. Manoj Mathur (MD)

Presented By – Lakshya Kumar

What is homocysteine : Homocysteine is a non-protein-forming, sulfur-

containing amino acid. It is an intermediary amino acid, which is

formed exclusively by demethylation of methionine, during conversion of methionine to cysteine.

There is no naturally occuring dietary

source of homocysteine.

(Ref :Clinical Biochemistry 36 (2003) 431–441)

METABOLISM OF HOMOCYSTEINE :

(Ref :Clinical Biochemistry 36 (2003) 431–441)

CAUSES OF HYPERHOMOCYSTEINEMIA :

Genetic enzyme deficiency – 5-Methyltetrahydrofolate reductase Cystathionine B-synthase Methionine synthase

Vitamin deficiency – Vitamin B12 Vitamin B6 Folate (Ref : ARCH INTERN MED/ VOL 158, JUNE 22, 1998)

cont..

Chronic medical disorders – Chronic renal failure Systemic lupus erythematosus Psoriasis Hypothyroidism Acute-phase response to systemic illness

Demographic – Increasing age Male

(Ref : ARCH INTERN MED/ VOL 158, JUNE 22, 1998)

cont…

Drugs – Methotrexate Antiepileptics ( phenytoin and carbamazepine) Colestipole Nicotinic acid Thizide diuretics Nitrous oxide Fibrates Metphormine Tabacco use/smoking (Ref : ARCH INTERN MED/ VOL 158, JUNE 22, 1998)

HOMOCYSTEINE — ITS IMPORTANCE IN VASCULAR DISEASE :

The relationship between hyperhomocysteinemia and atherosclerosis was suggested by McCully way back in 1969. (Ref : McCully K. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969;56:111-28.)

It took nearly thirty years to prove that raised levels of homocysteine is a risk factor for atherosclerosis.

It is now well accepted that elevated plasma homocysteine is a strong, graded, independent risk factor for stroke, myocardial infarction and other vascular events.

(Spence J, et al. Vitamin Intervention for Stroke Prevention Trial- An Efficacy Analysis. Stroke 2005;36:2404-9.)

:

In a meta-analysis of 27 trials, comparing

persons with homocysteine levels above the 90th percentile to the rest, the risk ratio for coronary artery disease was reported to be 1.7, for cerebrovascular disease 2.5, for peripheral vascular disease 6.8, and forvenous thrombosis 2.95.

It was estimated that a 5 mmol/L increment in homocysteine increased the CAD risk by as much as cholesterol increases of 20 mg/dL.

(Boushey C, et al. A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease. Probable Benefits of Increasing Folic Acid Intakes. JAMA 1995;274:1049-57.)

.

MECHANISM OF INJURY : (Ref : European Heart Journal (2000) 21, 967–974)

HYPERHOMOCYSTEINEMIA IN INDIANS :

Indian studies examining the prevalence of hyperhomocysteinemia in the community have reported a much higher incidence of 52 to 84% vs 5 to 7 % rate worldwide.

The mean homocysteine levels too are quiet high among indians varying from 19.5 to 23.2 micromols/L vs 4.4 to 10.8 micromols/L in worldwide.

(Wadia R, et al. Hyperhomocysteinemia and Vitamin B12 Deficiency in Ischaemic Strokes in India, Ann Ind Acad Neurol 2004;7:387-92.

Refsum H, et al. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr 2001;74:233-41.)

The reasons for the high incidence of hyperhomocysteinemia in Indians can be understand on the basis of metabolism of homocysteine (Fig. 1) : (Indian Study Group on Homocysteine – Consensus meeting on Hyperhomocysteinemia and Atherosclerosis, Goa, 24th June, 2006)

Firstly as Indians are often vegetarian, and

vegetarian food contains practically no vitamin B12, even milk contains small amounts of vitamin B12 but most of it is destroyed by boiling, so, amongst Indians, a dietary deficiency of the above mentioned homocysteine lowering B vitamins is often present.

In a recent study conducted in Pune, 441 middle aged men were examined, of which 149 came from rural areas, 142 from slums and 150 from urban middle class. Overall 67% of the men had low vitamin B12 concentration and 58% had hyperhomocysteinemia. In the urban middle class, 81% had low B12 and 79% had high homocysteine levels.

(Indian Study Group on Homocysteine – Consensus meeting on Hyperhomocysteinemia and Atherosclerosis, Goa, 24th June, 2006)

Vegetarians had a 4.4 times higher risk of low vitamin B12 than those who ate non - vegetarian food frequently and also a 3 times greater chance of hyperhomocysteinemia. (Indian Study Group on Homocysteine – Consensus meeting on Hyperhomocysteinemia and Atherosclerosis, Goa, 24th June, 2006)

Urban men were significantly more likely to have hyperhomocysteinemia than rural men.

(Yagnik C, et al. Vitamin B12 deficiency and Hyperhomocysteinaemia in Rural and Urban Indians JAPI 2006;54:775-81.)

Surprisingly, although majority of Indians are vegetarian, there is also a high incidence of folic acid deficiency reported. (Lakshmi A, et al. Plasma Homocysteine level in relation to folate and vitamin B6 status in apparently normal men. Asia Pacific J Clin Nutr 2001;10:194-5.)

The reason for this is that Indians usually cook their food for prolonged periods, which can destroy upto 90% of the folic acid. (SparkNotes: Water Soluble Vitamins: Folic Acid. www.sparknotes.com/health/vitamins/watersoluble.)

Pyridoxine deficiency is also reported to be quite common amongst Indians. (Gheye S, et al. Fibrinogen and Homocysteine levels in Coronary Artery Disease. Indian Heart J 1999;51:499-502.)

Second important factor that predisposes Indians to hyperhomocysteinemia is a genetic defect in the enzymes that metabolize homocysteine, especially MTHFR.

Studies have reported that upto one-third of Indians have a genetic defect which predisposes to decreased activity of MTHFR. (Mukherjee M, et al. A Low Prevalence of the C677T mutation in the methylenetetrahydrofolate Reductase Gene in Asian Indians. Clin Genet 2002;61:155-9. AND Kalita J, et al. Methykebetetrahydrofolate reductase gene polymorphism in Indian stroke patients. Neurology India 2006;54:260-3.)

Two polymorphisms of the MTHFR enzyme commonly exist amongst Indians viz. C677T and A1298C.

In a study where the presence of either of the polymorphism was examined, deficiency of MTHFR was reported in 43.5% of the population. (Kumar J, et al. Homocysteine levels are associated with MTHFR A1298C polymorphism in Indian Population. J Hum Geneta 2005;50:655-63.)

Compared to diet, however, the effect of

genetic factors in raising the homocysteine level seems to be modest.

Thus, the presence of a dietary deficiency of one or more of the vitamins involved in the metabolism of homocysteine superimposed on a background of MTHFR deficiency seems to be responsible for the very high incidence of hyperhomocysteinemia and the high homocysteine levels noticed in the Indian population.

(medicine_update_2007)

HYPERHOMOCYSTEINEMIA—IMPLICATIONS IN CARDIOLOGY :

Indians have been reported to have the highest incidence of CAD. (Enas E, et al. Dyslipidemia among Indo-Asians Strategies for Identification an Management. Br J Diabetes Vasc Dis 2005;5:81-90.)

The prevalence rate is almost 80-120 per 1000 population.

CAD also occurs more prematurely, often affecting people under the age of 40 years. (Yeolekar M, et al. Hyperhomocysteinemia and Vascular

Disease: Role and Implications. JAPI 2002;50:5-8.)

In one study Asian Indians were found to have significantly higher homocysteine levels than Europeans, which was believed to cause twice as many CAD deaths in Asian Indians as compared to Europeans. (Chambers J, et al. Plasma Homocysteine Concentrations and Risk of Coronary Heart Disease in UK Indian Asian and European. Lancet 2000;355:523-7.)

Hyperhomocysteinemia is now recognized to be an independent risk factor for atherosclerosis.

Homocysteine is an unstable amino acid, which undergoes autooxidation to produce free oxygen radicals.

Hyperhomocysteinemia, thus causes increased production of free oxygen radicals and an oxidative stress.

(Welch G, Loscalzo J. Homocysteine and Atherothrombosis. NEJM 1998;338:1042-50.)

This is believed to contribute to atherosclerosis in two ways (Fig. 2) : (medicine_update_2007)

Firstly, The free oxygen radicals convert LDLc deposited in the sub-endothelial tissue to oxidized LDLc (oxLDLc). OxLDLc then acts as the key mediator of the inflammatory process in atherosclerosis. (Kopprasch S, et al. In vivo evidence for increased oxidation of circulating LDL in impaired glucose tolerance. Diabetes 2002;51:3102-6.)

OxLDLc causes the release of vascular cell adhesion molecule (VCAM) and monocyte chemoattractant protein (MCP1), which in turn causes monocyte adhesion and penetration respectively.

The monocytes then get converted to macrophages, which take up oxLDLc to get converted to foam cells.

The foam cells get deposited below the endothelium to form a fatty streak, the first lesion in atherosclerosis.

(Welch G, Loscalzo J. Homocysteine and Atherothrombosis. NEJM 1998;338:1042-50.)

Secondly, the free oxygen radicals also combine with nitric oxide (NO), inactivating it to peroxynitrite and resulting in endothelial dysfunction,which also contributes significantly to atherosclerosis.

Hyperhomocysteinemia is associated with not just a greater risk of CAD but also with more severe disease and higher mortality.

In patients with CAD diagnosed by electron beam computed tomography (EBT), the coronary calcification over a period of a year progressed by 35% in patients with hyperhomocysteinemia as compared to just 17% in patients with normal homocysteine levels.

(Rasouli M, et al. Plasma Homocysteine Predicts Progression of Atherosclerosis. Atherosclerosis 2005;181:159-65.)

Homocysteine levels in CAD patients with triple vessel disease have been reported to be significantly higher than patients with single vessel disease. (Kobori Y, et al. Influence of Serum Homocysteine Level on Coronary Atherosclerosis. J Cardiol 2004;43:223-9.)

When patients with angiographically confirmed CAD were followed up for a period of 4 years, it was noticed that patients with hyperhomocysteinemia had 6 times greater mortality than patients with low homocysteine levels. (Nygard O, et al. Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease. NEJM, 1997;337:230- 6.)

It has been reported that the risk conferred by homocysteine, adds to or multiplies the risk conferred by other factors such as smoking, hypertension, diabetes and lipid disorders, all of which are common amongst Indians. (Reddy N, et al. Prevalence of risk factors for Coronary Atherosclerosis in a Cross-sectional Population of Andhra Pradesh. Indian Heart J 2002;54:697-701. and Ramchandran A, et al. Clustering of Cardiovascular risk factors in Urban Asian Indians. Diabetes Care 1998;21:967-71.)

In a study examining the synergy between hyperhomocysteinemia and hypercholesterolemia, it was reported that the presence of hyperhomocysteinemia in patients with hetrozygous familial hypercholesterolemia increased the risk of CAD by 5.7 times in men. (Pisciotta L, et al. Serum Homocysteine, Methylenetetrahydrofolate Reductase Gene Polymorphism and Cardiovascular Disease in Heterozygous Familial Hypercholesterolemia, Atherosclerosis 2005;179:333-8.)

Likewise, it has been reported that when hyperhomocysteinemia is present with smoking or 2 other risk factors, the CAD risk increases by 12 times and when present with increased Lipoprotein(a), the risk increases upto 30 times. (Enas E, et al. Dyslipidemia among Indo-Asians Strategies for Identification and Management. Br J Diabetes Vasc Dis 2005;5:81-90

In a study conducted at Jaslok hospital, Mumbai, homocysteine levels were examined in angiographically confirmed CAD patients (n=65) and compared with age matched controls (n=65).

The homocysteine levels were significantly elevated in the CAD patients as compared to controls.

CAD patients also had significantly low levels of vitamin B12 and folic acid.

(Personal Communication Dr.G.S.Sainani, Work done at Jaslok Hospital, Mumbai.)

Likewise, in a study conducted at Kanpur in young CAD patients, the incidence of hyperhomocysteinemia as well as mean homocysteine levels, were shown to be significantly higher in CAD patients as compared to controls.

(Puri A, et al. Homocysteine and Lipid Levels in Young Patients with Coronary Artery Disease. JAPI 2003;681-5.)

HYPERHOMOCYSTEINEMIA IMPLICATIONS IN DIABETOLOGY:

India tops the world diabetes list with 31.7 million diabetic patients and this is likely to rise to 79.4 million by the year 2030. (Wild, et al. Global Prevalence of Diabetes Mellitus. Diabetes Care 2004;27:1047-53.)

Over ninety percent of these have type 2 diabetes mellitus (T2DM). (Raheja B, et al. The DiabCare Asia–India Study Groups: Diabetes Care in India – Current Status. JAPI 2001;49:717-22.)

T2DM patients are frequently prone to atherosclerotic complications which account for more than 80% of all diabetic mortality. About three-fourths of these deaths are due to CAD. (Rao S, McGuire D. Epidemiology of Diabetes Mellitus and Cardio Vascular Disease. In: Marso SP, Stern DW (Eds). Diabetes and Cardio Vascular Disease. Lippincot, Williams and Wilkins, Philadelphia 2004;153-78.)

Diabetic patients have 2-4 times higher risk of CAD mortality as compared to the general population. (Pyorala K, et al. Diabetes and Atherosclerosis: An epidemiological view Diabetes Metab Rev 1987;3:463-524.)

Moreover, CAD has a few peculiarities in diabetic patients. CAD usually occurs earlier, progresses faster and is more diffuse.

Traditional risk factors often do not fully explain the higher cardiovascular mortality in T2DM patients. The increased risk might be due to the presence of other risk factors.

Hyperhomocysteinemia is one such risk factor.

Hyperhomocysteinemia is common in many diabetic patients and may contribute to the accelerated risk of atherosclerosis and cardiovascular disease. (Hu F, Manson D. Management of Diabetes: Diet and Lifestyle Modifications. In: Pickup JC, Williams G (Eds): Textbook of Diabetes. Blackwell Publishing Company, Malden, Massachusetts. 3rd Ed 2003;36-1:36-13.)

The exact cause of hyperhomocysteinemia in diabetic patients is not known.

Hyperhomocysteinemia has been shown to be associated with insulin resistance and obesity. (Meigs J, et al. Fasting Plasma Homocysteine levels in the Insulin Resistance Syndrome: The Framingham Offspring study. Diabetes Care 2001;24:1403-10. and Narin F, et al. The Association of Plasma Homocysteine Levels with Serum leptin and Apolipoprotein B levels in Childhood Obesity. Ann Saudi Med 2005;25:209-14.)

Decreased glomerular filtration and overt nephropathy, often present in diabetic patients, can contribute to hyperhomocysteinemia.

Some drugs like metformin and fenofibrate, commonly used in the management of diabetes, have also been reported to cause hyperhomocysteinemia.

It has been suggested that hyperhomocysteinemia caused by these drugs may negate some of their cardiovascular benefits. (Desouza C, et al. Drugs Effecting Homocysteine metabolism : Impact on Cardiovascular Risk. Drugs 2002;62:605-16. AND The Field Study Investigators, Effects of Long-term Fenofibrate Therapy on Cardiovascular Events in 9795 people with Type 2 Diabetes Mellitus (the FIELD Study) Randomized Controlled Trial. The Lancet 2005;366:1849-61.)

Both hyperhomocysteinemia and diabetes mellitus are individually known to increase the risk of cardiovascular disease. Hence, when present together, the risk is likely to increase further.

Moreover, patients with both T2DM and CAD co-existent, have been reported to have significantly higher homocysteine levels than patients with CAD alone or diabetes alone.

(Rudy A, et al. Homocysteine Concentrations and Vascular Complications I patients with Type 2 Diabetes. Diabetes Metab. 2005;31:112-7. AND Ndrepepa G, et al. Circulating Homocysteine Levels in Patients with type 2 Diabetes Mellitus. Nutr Metab Cardiovasc Dis. 4th October 2006.)

In a large population based study, the combined effects of hyperhomocysteinemia and diabetes mellitus were examined.

In this study, it was noticed that the presence of hyperhomocysteinemia increased the risk of cardiovascular disease by 1.6 times in diabetic subjects as compared to non-diabetic subjects. (Hoogeveen E, et al. Hyperhomocysteinemia is Associated With an Increased Risk of Cardiovascular Disease, Especially in Non- Insulin-Dependent Diabetes Mellitus. A Population-Based Study. Arterioscler Thromb Vasc Biol 1998;18:133-8.)

Hyperhomocysteinemia has also been reported to be a predictor of CAD severity in T2DM.

In a study carried out in T2DM patients with stenotic coronary arteries, the degree of coronary artery stenosis was noticed to be related to the serum homocysteine levels.

Patients with triple vessel disease had significantly higher homocysteine levels as compared to patients with two vessels or single vessel disease (16.1, 14.0 and 12.7 μmols/L respectively).

(Okada E, et al. Hyperhomocysteinemia is a Risk Factor for Coronary Arteriosclerosis in Japanese Patients with Type 2 Diabetes. Diabetes Care 1999;22:484-90.)

In one study, the effect of hyperhomocysteinemia on fatal and non-fatal CAD events in T2DM patients was examined.

It was noticed that diabetic patients with hyperhomocysteinemia, had a two times greater risk of CAD deaths as compared to diabetic patients whose homocysteine levels were less than 15 μmols/L (26.1% vs. 13.5%). Also the risk of CAD events was 36.2% and 26.2% respectively.

This study concluded that in T2DM patients, hyperhomocysteinemia was a strong and independent risk factor for CAD events.

(Soinio M, et al. Elevated Plasma Homocysteine Level Is an Independent Predictor of Coronary Heart Disease Events in Patients with Type 2 Diabetes Mellitus. Ann Intern Med 2004;140:94-100.)

In the Hoorn study, the effect of hyperhomocysteinemia on the five year mortality in diabetic patients was compared to non-diabetic patients.

For each 5 μmols/L rise in homocysteine levels, the risk of 5 year mortality rose by 17% in non-diabetic and 60% in diabetic subjects.

Thus, hyperhomocysteinemia appeared to be a stronger (1.9 fold) risk factor for mortality in type 2 diabetic patients than in non-diabetic patients.

(Hoogeveen E, et al. Hyperhomocysteinemia increases Risk of Death especially in Type 2 Diabetes: 5 year follow up of the Hoorn Study. Circulation 2000;101:1506-11.)

Very few studies conducted in India have examined the incidence of hyperhomocysteinemia in diabetic patients.

In one study conducted in Pune, hyperhomocysteinemia was recorded in 76% of diabetic patients as compared to 81% in the community. (Refsum H, et al. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr 2001;74:233-41.)

Likewise, in a study conducted at Dr Talwalkar Clinic, Mumbai, the incidence of hyperhomocysteinemia in the diabetic patients was 68% as against 70% in the community. (Keshvani A, Talwalkar P. Homocysteine Levels in patients with T2DM and Vascular Complications. Paper presented at RSSDI Mahacon, 15th March 2005 – Thane.)

A study conducted at Jaslok hospital, Mumbai, recorded significantly higher homocysteine levels in diabetic patients as compared to controls. (Ridker P, et al. Plasma Homocysteine Concentration, Statin Therapy and the Risk of First Acute Coronary Events. Circulation 2002;105:1776-9.)

Thus, the incidence of hyperhomocysteinemia as well as mean homocysteine level is quite high in Indian diabetic patients.

In the west, although the incidence of hyperhomocysteinemia in diabetic patients has been reported to be much higher than the community, it is likely that hyperhomocysteinemia develops after the onset of diabetes and then interacts with it to worsen the CAD prognosis.

On the other hand, in Indian diabetic patients, as the incidence of hyperhomocysteinemia in the community itself is high, hyperhomocysteinemia is probably already present when the patient develops diabetes.

Hence, hyperhomocysteinemia is likely to interact with diabetes from the very beginning and cause greater deleterious effects.

T2DM patients frequently have both hyperhomocysteinemia and dyslipidemia coexistent. (Gazzaruso C, et al. Silent Coronary Artery Disease in Type 2 Diabetes Mellitus: the role of Lipoprotein(a), Homocysteine and apo(a) Polymorphism. Cardiovascular Diabetology 2002;1:5. )

In one small pilot study conducted at Dr Talwalkar clinic, Mumbai, the benefits of adding homocysteine lowering vitamins to atorvastatin on the progression of atherosclerosis in diabetic patients was examined.

High risk diabetic patients with increased carotid artery intima media thickness (IMT) were randomized to receive either atorvastatin 10 mg or atorvastatin10 mg along with three homocysteine lowering vitamins, viz. methylcobalamin 500 mcg, folic acid 5 mg and pyridoxine 10 mg.

The treatment was continued for a period of one year.

In patients who received atorvastatin alone, the mean IMT progressed from 0.88 to 0.92 mm; whereas in those who received homocysteine lowering vitamins along with atorvastatin, there was no progression of IMT. (Keshvani A, Athavale U, Talwalkar P. Comparative Effect of Atorvastatin and Atorvastatin with Homocysteine Lowering Vitamins on Carotid Intima Media Thickness in patients with Type-2 Diabetes Mellitus. Paper to be presented at IDF Capetown 7th December 2006.)

Therefore, it may be prudent to estimate homocysteine levels in all diabetic patients and if the levels are found to be more than 12 mmols/L, homocysteine lowering vitamins, which are safe and inexpensive, should be administered.

HYPERHOMOCYSTEINEMIA – IMPLICATIONS IN NEUROLOGY :

Hyperhomocysteinemia has been shown to be associated with a number of neurological conditions like stroke,silent brain infarct, dementia, movement disorders, etc.

Hyperhomocysteinemia and Stroke-The

Ruby Hall Study : (Wadia R, et al. Hyperhomocysteinemia and Vitamin B12 Deficiency in Ischaemic Strokes in India. Ann Ind Acad Neurol 2004;7:387-92.)

At the Ruby Hall Clinic, Pune, serum homocysteine, B12 and folate were estimated in consecutive cases of ischemic stroke, arterial or venous infarction.

The exclusion criteria included embolic stroke unless it was due to CAD, renal disease, hypothyroidism or those on vitamin supplements or injections of B12/folate.

As seen in Table 1, 80.74% of all arterial stroke had raised homocysteine and 75% of venous infarcts had the same. A raised homocysteine was the commonest risk factor for stroke in this population.

The mean homocysteine in vegetarians with stroke was 37.7 + 11.9 μmols/L and the mean homocysteine level in all non vegetarians from rare to more than once a week was 25.5 + 13.6 μmols/L in this population.

The Ruby Hall Study is by far the largest Indian study in stroke. However, several other neurologists in Pune, Mumbai, Guwahati and Hyderabad have reported similar findings.

In a study conducted in Guwahati recently, hyperhomocysteinemia was reported in 59.1% of 110 ischemic stroke. (Das R, Borah N C. Homocysteine and Ischaemic stroke a case control study. Annals of Indian Academy of Neurology 2006; 9(Supplement 1):39.)

Likewise, hyperhomocysteinemia was reported in 83% of the 58 patients with ischemic stroke studied in Lucknow. (Kalita J, et al. Methykebetetrahydrofolate reductase gene polymorphism in Indian stroke patients. Neurology India 2006;54:260-3.)

Homocysteine levels, Silent Brain Infarcts and White Matter Lesions in the Elderly :

The Rotterdam scan study examined elderly people between the ages of 60 and 99. These patients were stratified based on their serum homocysteine into quartiles and the changes seen in the lowest quartile were taken as standard. (Vermeer S, et al. Homocysteine, silent brain infarcts and white matter lesions. The Rotterdam Scan study Annals Neurol 2002; 51:385-9.)

Compared to the lowest quartile, each higher quartile showed an increase in changes.

The rate of the changes in the top quartile was 2.5 times that in the lowest quartile for silent brain infarcts, 2.3 times for severe white matter changes and 3 times more if both silent brain infarcts and white matter changes were included.

Thus, sub-clinical sub-cortical ischemia usually due to small vessel disease is also associated with significantly raised homocysteine levels.

Homocysteine and Dementia :

The topic of homocysteine and dementia was opened up by a report of the association from the Framingham study, in which 1092 elderly persons without dementia were followed up for 8 years. The serum was available for estimation of serum homocysteine at the onset and 8 years after the start of the study.

In follow up 111 persons developed dementia. It was found that those in the highest quintile (top 1/5) of serum homocysteine had an increased risk of developing dementia.

(Seshadri S, et al. Plasma Homocysteine as a risk factor for dementia and Alzheimer’s disease. New Eng J Med 2002; 346: 476-83.)

The highest quintile, compared to all other quintiles at the end of 8 years, had a 1.9 times greater chance of developing dementia and this risk was not only for vascular dementia but also for Alzheimer’s dementia.

Thus, high homocysteine levels, preceded the onset of dementia, by years.

(Seshadri S, et al. Plasma Homocysteine as a risk factor for dementia and Alzheimer’s disease. New Eng J Med 2002; 346: 476-83.)

In a study conducted in Japan, it was pointed out that Alzheimer’s disease patients also had increased silent brain infarct (SBI).

Of the 143 cases of Alzheimer’s disease, 47 (32.9%) had silent brain infarct (SBI).

The homocysteine levels in the ones with SBI were significantly higher than in those without.

(Matsui T, Nemolo M, Muruyama M. Plasma Homocysteine and risk of co existing silent Brain infarcts in Alzheimer’s disease Neuro deger Dise 2005;2:299-304.)

SCREENING FOR HYPERHOMOCYSTEINEMIA :

Atherosclerotic vascular disease without conventional risk factors

Premature atherosclerotic vascular disease (before age of 60 yrs)

High risk for premature atherosclerotic vascular disease-

First-degree relatives with premature atherosclerotic vascular disease

Tabacco use Diabetes mallitus Hypertension (Ref : ARCH INTERN MED/ VOL 158, JUNE 22, 1998)

cont…

Chronic renal failure Unexplained deep vein thrombosis Systemic lupus erythematosus Solid organ transplant recipients Severe psoriasis Use of homocysteine-raising drugs.

(Ref : ARCH INTERN MED/ VOL 158, JUNE 22, 1998)

TREATMENT :The internationally accepted treatment for

hyperhomocysteinemia involves the use of three homocysteine lowering vitamins viz. folic acid, vitamin B12 and pyridoxine.

Folic acid and B12 act predominantly under fasting conditions and pyridoxine acts after meals.

In patients with hyperhomocysteinemia, folic acid alone was shown to reduce homocysteine levels by 22% and vitamin B12 by 11%. However, when both were administered together, they acted synergistically to cause a reduction in the homocysteine levels by 38.5%.

(Sato Y, et al. Hyperhomocysteinemia in Japanese patients with convalescent stage ischemic

stroke: Effect of combined therapy with folic acid and mecobalamine, J Neurol Sci 2002;202:65-8.)

Pyridoxine has been shown to cause a reduction in the post methionine loading homocysteine levels by 22%. (Bostom A, et al. Treatment of hyperhomocysteinemia in renal transplant recipients. A randomized, placebo-controlled trial. Ann Intern Med 1997;127:1089-92.)

Evidence that high serum homocysteine is a risk factor for CAD, stroke and vascular dementia is now very convincing. The important question is whether lowering homocysteine will reduce risk for subsequent stroke or myocardial event???

The first study in this regard was the Swiss heart study, which followed up 553 patients after successful angioplasty.

One group received homocysteine lowering vitamins and one did not.

There was a significant reduction in the need for re-vascularization in the supplemented group than those without.

Mortality and second non-fatal MI was also less in the supplemented group but this did not reach statistical significance. (Schnyder G, et al. Effect of homocysteine-lowering therapy with folic acid, vitamin b(12), and vitamin B(6) on clinical outcome after percutaneous coronary intervention : the Swiss Heart study: a randomized controlled trial. JAMA 2002;288:973-9.)

In another study examining the effect of homocysteine lowering vitamins on the endothelial function in patients with CAD, administration of the vitamins for a period of six months was shown to improve the endothelial function and increase the coronary blood flow by 96% as compared to a further reduction in coronary blood flow by 16% in patients who received the placebo.

Benefits of homocysteine lowering vitamins have also been noticed on the carotid artery intima media thickness (IMT).

In patients with hyperhomocysteinemia and increased IMT, homocysteine lowering vitamins reduced the IMT from 1.50 to 1.42 mm, whereas in those receiving placebo, the IMT increased from 1.47 to 1.54 mm. (Till U, et al. Decrease of carotid intima-media thickness in patients at risk to cerebral ischemia after supplementation with folic acid, Vitamin B6 and B12. Atherosclerosis 2005;181:131-5.)

VISP trial (Vitamin Intervention for Stroke Prevention) was published in 2004. It was a double blind controlled trial.

In this study it was found that the high dose B12 supplement group had 21% less risk of death, stroke, or coronary heart disease.(Spence JD, et al. Vitamin intervention for stroke prevention trial an efficacy analysis. Stroke 2005;36:2404-9.)

The HOPE 2 (HEART OUTCOMES PREVENTION EVALUATION) study randomized 5522 persons age 55 and older to receive vitamin supplements or placebo.

In this study, the mean homocysteine before treatment in both groups was 12.2 μmols/L and after 5 years treatment in the control group it had risen to 12.9 and in the treatment group homocysteine had fallen to 9.7, leaving a 3.2 μmols/L difference in the two groups.

And it was found that, homocysteine lowering vitamins reduced the risk of all stroke by 25% and non fatal stroke by 28%.

(The heart outcomes prevention evaluation (HOPE) 2 investigators, Homocysteine lowering

with folic acid and B vitamins in vascular disease. NEJM 2006;354:1566-77.)

In India the conditions are quite different than in the US and other countries where the HOPE 2 study was done.

In the HOPE 2 study, before treatment the mean Hcy level was 12.2 μmols/L while in Ruby Hall study, the pure vegetarian control group had homocysteine levels of 27.7 μmols/L and the occasional non-vegetarians had homocysteine levels of 21.0 μmols/L.

The mean B12 level in the HOPE 2 study patients was 426-436 μmols/L while in Ruby Hall Study vegetarian controls had mean B12 levels of 190 μmols/L and 56% of the pure lacto-vegetarian and 55% of occasional non-vegetarians had B12 deficiency.

At Ruby Hall Study the homocysteine falls in stroke patients after treatment reached 30 μmols/L(39.7-9.8 μmols/L over 2-8 months).

Thus the HOPE 2 study results probably do not apply to the Indian population.

Perhaps the most striking results of vitamin supplementation come from the study of stroke epidemiology in US and Canada from 1990-2002.

In the US, from 1990- 98, stroke mortality was falling steadily at 0.3% per year. After 1998, when folate substitution in cereals was introduced, the mortality fell to 2.9% per year, a 10 times change.

(Yang Q, et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 2006;113:1335-43.)

So, if food fortification is tried in India, one should also have to fortify with vitamin B12, not just folate, and find a universally used food which could be fortified.

Until such time, doctors should remember that raised homocysteine is a very common and important cardiovascular risk factor in our country, commoner than diabetes, smoking and even hypertension and carrying the same risk roughly as each of the 3 above, and it is the easiest of the risk factors to modify.